Excitotoxicity has been postulated to underlie the neurodegeneration that frequently accompanies systemic AIDS. This proposal addresses the overall question of how HIV-1 proteins, chemokines and drugs of abuse influence glutamatergic synaptic transmission and how the Ca2+ load that results from aberrant patterns of synaptic activity triggers neurotoxicity. Optical, electrophysiological and gene transfer techniques will be directed toward three specific aims. 1) The effects of chemokines and the HIV-1 envelope protein (gp120) on microglia and neurons grown in primary culture will be determined. The hypothesis that gp120 will interfere with chemokine-mediated signaling in microglia, inducing the release of factors that excite synaptic networks and produce neuronal death will be tested. These experiments will clarify the role of microglia in HIV-1 neurotoxicity and may identify pharmacologic targets that could influence the course of AIDS dementia complex. 2) The effects of cannabinoids on glutamatergic synaptic activity will be determined. The hypothesis that inhibition of synaptic transmission by cannabimimetic drugs will desensitize as a function of agonist efficacy and intrinsic activity of partial agonists will be dependent upon the specific synapse will be tested. These studies will provide insight into the synaptic mechanisms of cannabimimetic drugs. 3) The role of the mitochondrion in NMDA-induced, Ca2+-mediated neurotoxicity will be determined. The hypothesis that the uptake of NMDA-induced Ca2+ loads into mitochondria can be modulated and that conditions that reduce matrix Ca2+ levels will be neuroprotective will be tested. Understanding the fate of toxic Ca2+ loads and how sequestration can be modulated will provide tools to better study Ca2+-induced cell death and may identify targets for neuroprotection. Overall, these studies are directed specifically towards understanding AIDS neurotoxicity and its modulation by drugs of abuse, in addition, they will contribute more generally to understanding chemokine function in the CNS, the modulation of synaptic activity by G-protein-coupled receptors and the relationship between aerobic metabolism and Ca2+ homeostasis.